Frequency of gene polymorphisms and association with genotype and phenotype in 107 donor-recipient pairs
| Gene (point mutation) . | Genotype . | Associated phenotype . | No. patients (%) . | No. donors (%) . |
|---|---|---|---|---|
| TNF-α (−308) | ||||
| AA | Higher production* | 2 (1) | 2 (1) | |
| AG | — | 22 (21) | 23 (22) | |
| GG | Lower production | 83 (78) | 82 (77) | |
| TNF-β (−252) | ||||
| GG | Higher production* | 10 (9) | 10 (9) | |
| AG | — | 30 (28) | 31 (29) | |
| AA | Lower production | 67 (63) | 66 (62) | |
| IL-1RN (IL-1 Ra) (VNTR) | ||||
| A1/A1 | — | 60 (56) | 55 (51) | |
| A1/A2 (IL-1RN*2) | Higher production† | 38 (35) | 39 (36) | |
| A1/A3 | — | 3 (3) | 5 (5) | |
| A2/A2 (IL-1RN*2) | Higher production | 6 (6) | 8 (7) | |
| IL-6 (−174) | ||||
| GG | Higher production* | 49 (46) | 42 (39) | |
| GC | — | 44 (41) | 51 (48) | |
| CC | Lower production | 14 (13) | 14 (13) | |
| IL-10 (−1082) | ||||
| AA | Lower production* | 34 (32) | 34 (32) | |
| AG | — | 50 (47) | 47 (44) | |
| GG | Higher production | 23 (21) | 26 (24) | |
| PECAM-1 or CD31 | ||||
| L/L | Not applicable‡ | 27 (25) | 26 (24) | |
| V/L | Not applicable‡ | 55 (51) | 62 (58) | |
| V/V | Not applicable‡ | 25 (23) | 19 (18) | |
| ICAM-1 or CD54 | ||||
| AA | Not applicable‡ | 104 (97) | 103 (96) | |
| AT | Not applicable‡ | 2 (2) | 4 (4) | |
| TT | Not applicable‡ | 1 (<1) | — | |
| FcγRIIa or CD32 (−131) | ||||
| H/H | Higher affinity for human IgG2, IgG32-153 | 29 (27) | 24 (22) | |
| R/H | — | 61 (57) | 58 (54) | |
| R/R | — | 17 (16) | 25 (23) | |
| FcγRIIIa or CD16a (−559) | ||||
| G/G | Higher affinity for IgG1 and IgG32-153 | 22 (21) | 18 (17) | |
| G/T | — | 44 (41) | 51 (48) | |
| T/T | — | 40 (38) | 37 (35) | |
| FcγRIIIb or CD16b | ||||
| HNA-1a/1a (NA1/NA1) | Higher affinity for immune-complexed IgG3 and lower levels of sFCγRIIIb2-153 | 12 (11) | 13 (12) | |
| HNA-1a/1b (NA1/NA2) | — | 51 (49) | 42 (40) | |
| HNA-1b/1b (NA2/NA2) | — | 42 (40) | 50 (48) | |
| MBL | ||||
| AA | — | 80 (76) | 75 (73) | |
| AB, AC, AD | Decreased serum concentration2-155 | 24 (23) | 23 (23) | |
| Non-A | Undetectable in serum | 1 (<1) | 4 (4) | |
| MPO (−463) | ||||
| GG | — | 59 (55) | 64 (60) | |
| AG | Decreased intracellular concentration2-154 | 35 (33) | 37 (35) | |
| AA | Decreased intracellular concentration | 13 (12) | 6 (5) |
| Gene (point mutation) . | Genotype . | Associated phenotype . | No. patients (%) . | No. donors (%) . |
|---|---|---|---|---|
| TNF-α (−308) | ||||
| AA | Higher production* | 2 (1) | 2 (1) | |
| AG | — | 22 (21) | 23 (22) | |
| GG | Lower production | 83 (78) | 82 (77) | |
| TNF-β (−252) | ||||
| GG | Higher production* | 10 (9) | 10 (9) | |
| AG | — | 30 (28) | 31 (29) | |
| AA | Lower production | 67 (63) | 66 (62) | |
| IL-1RN (IL-1 Ra) (VNTR) | ||||
| A1/A1 | — | 60 (56) | 55 (51) | |
| A1/A2 (IL-1RN*2) | Higher production† | 38 (35) | 39 (36) | |
| A1/A3 | — | 3 (3) | 5 (5) | |
| A2/A2 (IL-1RN*2) | Higher production | 6 (6) | 8 (7) | |
| IL-6 (−174) | ||||
| GG | Higher production* | 49 (46) | 42 (39) | |
| GC | — | 44 (41) | 51 (48) | |
| CC | Lower production | 14 (13) | 14 (13) | |
| IL-10 (−1082) | ||||
| AA | Lower production* | 34 (32) | 34 (32) | |
| AG | — | 50 (47) | 47 (44) | |
| GG | Higher production | 23 (21) | 26 (24) | |
| PECAM-1 or CD31 | ||||
| L/L | Not applicable‡ | 27 (25) | 26 (24) | |
| V/L | Not applicable‡ | 55 (51) | 62 (58) | |
| V/V | Not applicable‡ | 25 (23) | 19 (18) | |
| ICAM-1 or CD54 | ||||
| AA | Not applicable‡ | 104 (97) | 103 (96) | |
| AT | Not applicable‡ | 2 (2) | 4 (4) | |
| TT | Not applicable‡ | 1 (<1) | — | |
| FcγRIIa or CD32 (−131) | ||||
| H/H | Higher affinity for human IgG2, IgG32-153 | 29 (27) | 24 (22) | |
| R/H | — | 61 (57) | 58 (54) | |
| R/R | — | 17 (16) | 25 (23) | |
| FcγRIIIa or CD16a (−559) | ||||
| G/G | Higher affinity for IgG1 and IgG32-153 | 22 (21) | 18 (17) | |
| G/T | — | 44 (41) | 51 (48) | |
| T/T | — | 40 (38) | 37 (35) | |
| FcγRIIIb or CD16b | ||||
| HNA-1a/1a (NA1/NA1) | Higher affinity for immune-complexed IgG3 and lower levels of sFCγRIIIb2-153 | 12 (11) | 13 (12) | |
| HNA-1a/1b (NA1/NA2) | — | 51 (49) | 42 (40) | |
| HNA-1b/1b (NA2/NA2) | — | 42 (40) | 50 (48) | |
| MBL | ||||
| AA | — | 80 (76) | 75 (73) | |
| AB, AC, AD | Decreased serum concentration2-155 | 24 (23) | 23 (23) | |
| Non-A | Undetectable in serum | 1 (<1) | 4 (4) | |
| MPO (−463) | ||||
| GG | — | 59 (55) | 64 (60) | |
| AG | Decreased intracellular concentration2-154 | 35 (33) | 37 (35) | |
| AA | Decreased intracellular concentration | 13 (12) | 6 (5) |
sFcγR indicates soluble FcγR; H, histidine; R, arginine; L, leucine; and V, valine.
A, G, C, and T are DNA bases.
Polymorphisms within the genes of TNF-α (−308), TNF-β (−252), IL-6 (−174), and IL-10 (−1082) have been linked to various degrees of production of their respective proteins.14 26-28
The IL-1 gene cluster contains 3 related genes—IL-1A, IL-1B, and IL-1RN—that encode the proinflammatory cytokines IL-1α and IL-1β and their endogenous receptor antagonist IL-1Ra, respectively.29 The IL-1RN gene has an 86-bp tandem repeat (VNTR) in intron 2, of which the less common allele 2 (IL-1RN*2) is associated with a wide range of chronic inflammatory and autoimmune conditions and increased risk for gastric cancer.30 IL-1RN*2 is associated with enhanced IL-1β production in vitro,31 but its effects on IL-1Ra production are contradictory.32-34
Adhesion molecule (PECAM-1 and ICAM-1) gene polymorphisms are not associated with a specific phenotype. In some studies, PECAM-1 or CD31 gene polymorphisms have been associated with aGVHD35,36and those of ICAM-1 with susceptibility to malaria.37
Polymorphisms of Fcγ receptors (FcγR) FcγRIIa (CD32), FcγRIIIa (CD16a), and FcγRIIIb (CD16b) critically affect interaction with antibodies. Polymorphisms of FcγRIIa affect receptor affinity and specificity when a G>A point mutation results in an arginine (Arg) or a histidine (His) residue at position 131 in the membrane proximal immunoglobulinlike domain.38-40FcγRIII is expressed on macrophages and lymphoid cells as a transmembrane receptor (FcγRIIIa) and as a GPI-linked molecule (FcγRIIIb) on neutrophils. A G>T point mutation at nucleotide 559 (559G>T) within FcγRIIIa results in an amino acid substitution at position 158 (valine to phenylalanine, Val158Phe) in immunoglobulinlike domain 2, reflecting different affinities for IgG1 and IgG3. FcγRIIIb represents the most abundant FcR on neutrophils. The FcγRIIIb-HNA1a (or NA1) and HNA1b (or NA2) isoforms differ by 4 amino acids in the membrane distal immunoglobulinlike domain, resulting in different patterns of glycosylation41 and affecting ligand affinity. It has also been demonstrated that FcγRIIIb-HNA-1b homozygous donors contain higher levels of soluble FcγRIIIb (sFcγRIIIb) than do HNA-1a homozygous donors.42
Human deficiency of MBL is known to be predominantly caused by point mutations within exon 1 of the MBL gene at codon 52, 54, or 57 (termed D, B, and D variants, respectively) that result in amino acid substitutions that compromise assembly of functional oligomers.43 Patients heterozygous for these mutations have reduced concentrations of MBL in serum, whereas the protein is almost absent from the serum of homozygous and compound heterozygous patients.44
MPO is an enzyme found primarily in the lysosomes of neutrophils. A single-base substitution (G>A) in an Alu repeat in the promoter region of the MPO gene, 463 bases upstream from the MPOgene, decreases expression, apparently by destroying a binding site for the SPI transcription factor.45